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PubMed2006

Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway.

Nuclear factor (NF)-kappaB is important in the generation of inflammation. Besides regulating lipid metabolism, peroxisome proliferator-activated receptor (PPAR)-alpha activators also reduce NF-kappaB activation to terminate activation of inflammatory pathways. Gynostemma pentaphyllum (GP) has been used to treat various inflammatory diseases and hyperlipidemia. Here, we demonstrate that GP extract and one of its main components, Gypenoside XLIX (Gyp-XLIX) inhibited LPS-induced NF-kappaB activation in murine macrophages. Furthermore, Gyp-XLIX restored the LPS- and TNF-alpha-induced decrease in cytosolic I-kappaBalpha protein expression and inhibited the translocation of NF-kappaB(p65) to the nucleus in THP-1 monocyte and HUVEC cells. The inhibition of LPS- and TNF-alpha-induced NF-kappaB luciferase activity in macrophages was abolished by MK-886, a selective PPAR-alpha antagonist. GP extract and Gyp-XLIX (EC(50): 10.1 microM) enhanced PPAR-alpha luciferase activity in HEK293 cells transfected with the tK-PPREx3-Luc reporter plasmid and expression vectors for PPAR-alpha. Additionally, Gyp-XLIX specifically enhanced PPAR-alpha mRNA and protein expression in THP-1-derived macrophage cells. The selectivity of Gyp-XLIX for PPAR-alpha was demonstrated by the activation of only PPAR-alpha in HEK293 cells transfected with expression vectors for PPAR-alpha, PPAR-beta/delta or PPAR-gamma1 plasmids and in THP-1-derived macrophage naturally expressing all three PPAR isoforms. The present study demonstrates that Gyp-XLIX, a naturally occurring gynosaponin, inhibits NF-kappaB activation via a PPAR-alpha-dependent pathway.

Analysis of Variance↗
PubMed2001

Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation.

Peroxisome proliferator-activated receptor (PPAR)-alpha agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-gamma activation. Three-week high fat-fed male Wistar rats were untreated or treated with the specific PPAR-alpha agonist WY14643 or the PPAR-gamma agonist pioglitazone (both 3 mg x kg(-1) x day(-1)) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced whole-body insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulin-mediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-alpha and PPAR-gamma activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation.

Animals↗
PubMed2006

PPAR-alpha and -gamma agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-alpha agonist, gemfibrozil, the PPAR-gamma agonist rosiglitazone and the non-thiazolidinedione PPAR-alpha/gamma coagonist, compound 3q, on kidney structure and function in streptozotocin-treated apolipoprotein E knockout mice. METHODS: Control and streptozotocin-diabetic mice were randomized to receive rosiglitazone (20 mg/kg/day), gemfibrozil (100 mg/kg/day), or compound 3q (3 mg/kg/day) by gavage, or no treatment for a period of 20 weeks. Renal fibrosis was assessed by standard histology and collagen IV immunohistochemistry. Kidney function was assessed by urinary albumin excretion and creatinine clearance. RESULTS: Diabetes in this model was associated with an increase in glomerulosclerosis, tubulointerstitial fibrosis and increased collagen IV deposition in the glomeruli and tubules. All three agents significantly attenuated glomerulosclerosis, tubulointerstitial expansion and collagen IV deposition. The increase in albuminuria and the decline in kidney function associated with diabetes in this model were also attenuated by each of these agents, with no superiority observed among various treatment groups. These renoprotective effects were observed in the absence of changes in glucose, insulin or lipid levels or a reduction in blood pressure. CONCLUSIONS: Combined with their independent anti-atherosclerotic actions, and their important effects on dyslipidaemia and insulin resistance, PPAR agonists may be useful for the prevention of diabetic complications, including kidney disease, even in type 1 diabetes.

Animals↗
PubMed2006

Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical and experimental evidence.

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)-alpha is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR-alpha is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR-alpha agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR-alpha agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR-alpha activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR-alpha agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Animals↗
PubMed2003

PPAR-alpha and -gamma but not -delta agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independent effect.

1. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have been proposed to regulate inflammation by antagonising the nuclear factor-kappaB (NF-kappaB) signalling pathway. We investigated the role of PPARs using synthetic agonists in murine models of airway inflammation, and addressed the possible effect on NF-kappaB signalling in vitro using a human epithelial cell line, A549. 2. Sensitised BALB/c mice exposed to an aerosol solution of ovalbumin had an increased number of airway eosinophils, neutrophils and lymphocytes. When given intranasally an hour before the aerosol challenge, a PPAR-alpha (GW 9578) and PPAR-gamma (GI 262570) selective agonist as well as a dual PPAR-alpha/gamma (GW 2331) agonist selectively inhibited allergen-induced bronchoalveolar lavage eosinophil and lymphocyte but not neutrophil influx. In contrast, a PPAR-delta agonist (GW 501516) was inactive. 3. When given intranasally an hour before challenge, PPAR-alpha and PPAR-gamma selective agonists as well as a dual PPAR-alpha/gamma agonist did not inhibit lipopolysaccharide-induced bronchoalveolar lavage neutrophil influx or tumour necrosis factor-alpha (TNF-alpha) and KC production. 4. In A549 cells, selective agonists for PPAR-alpha, -gamma and -delta did not inhibit intracellular adhesion molecule-1 expression following stimulation with proinflammatory cytokines. In addition, IL-8 release and the activation of an NF-kappaB-responsive reporter gene construct were inhibited only at micromolar concentrations, suggesting that these effects were not PPAR-mediated. 5. Our in vivo data show that agonists of PPAR-alpha and -gamma, but not -delta, inhibit allergen-induced bronchoalveolar lavage eosinophil and lymphocyte influx. In vitro data suggest that this effect might not be mediated by antagonism of the NF-kappaB pathway.

Animals↗
PubMed2003

PPAR-alpha effects on the heart and other vascular tissues.

Peroxisome proliferator-activated receptor (PPAR)-alpha is a member of a large nuclear receptor superfamily whose main role is to activate genes involved in fatty acid oxidation in the liver, heart, kidney, and skeletal muscle. While currently used mainly as hypolipidemic agents, the cardiac effects and anti-inflammatory actions of PPAR-alpha agonists in arterial wall cells suggest other potential cardioprotective and antiatherosclerotic effects of these agents. This review summarizes current knowledge regarding the effects of PPAR-alpha agonists on lipid and lipoprotein metabolism, the heart, and the vessel wall and introduces some of the insights gained in these areas from studying PPAR-alpha-deficient mice. The introduction of new and more potent PPAR-alpha agonists will provide important insights into the overall benefits of activating PPAR-alpha clinically for the treatment of dyslipidemia and prevention of vascular disease.

Animals↗
PubMed1997

PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents.

The nuclear receptor PPAR alpha is a key regulatory transcription factor in lipid homeostasis, some liver detoxification processes and the control of inflammation. Recent findings suggest that many hypolipidemic drugs and anti-inflammatory agents can potentially act by binding to PPAR alpha and inducing its activity. Here, we identify some structure-function relationships in PPAR alpha, by using the species-specific responsiveness to the two hypolipidemic agents, Wy 14,643 and 5,8,11,14-eicosatetraynoic acid (ETYA). We first show that the species-specific differences are mediated primarily via the ligand binding domain of the receptor and that these two drugs are indeed ligands of PPAR alpha. By mutagenesis analyses we identify amino acid residues in the ligand binding domains of Xenopus, mouse and human PPAR alpha, that confer preferential responsiveness to ETYA and Wy 14,643. These findings will aid in the development of new synthetic PPAR alpha ligands as effective therapeutics for lipid-related diseases and inflammatory disorders.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2001

Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886.

Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Animals↗
PubMedDate not supplied

Expression of PPAR(alpha) in human hepatocytes and activation by trichloroacetate and dichloroacetate.

Dichloroacetate (DCA) and trichloroacetate (TCA) are carcinogenic metabolites of trichloroethylene (TCE), a known hepatocarcinogen in B6C3F1 mice. This hepatocarcinogenesis is believed to result from peroxisome proliferation via PPAR(alpha) and/or stimulation of hepatocyte replication. In this study hPPAR(alpha) levels in six human liver tissues and in a long-term human hepatocyte cell line are compared. PPAR(alpha) levels varied significantly between individual tissues and are generally lower than PPAR(alpha) levels detected in mouse liver. Long-term cultured human hepatocytes display PPAR(alpha) levels only slightly lower than cultured mouse hepatocytes. Transfection studies examining the endogenous hPPAR(alpha) activity revealed little or no receptor activation, even following treatment with high concentrations of peroxisome proliferators. In contrast human hepatocytes transfected with mPPAR(alpha) and mRXR(alpha) display increased expression of PPAR(alpha), and increased PPRE-reporter activity when treated with WY-14,643, TCA, and DCA. This human hepatocyte transfection system is a promising tool for examinin the regulation of genes by PPAR(alpha) from different species.

Biotransformation↗
PubMed2003

Peroxisome proliferator activated receptor (PPAR)alpha agonists inhibit hypertrophy of neonatal rat cardiac myocytes.

The peroxisome proliferator activated receptors (PPARs) appear to have beneficial effects in the cardiovascular system. PPAR gamma has been shown previously to exert an inhibitory effect on cardiac myocyte hypertrophy in vivo and in vitro. Using endothelin to activate the hypertrophic program in neonatal rat cardiac myocytes, we demonstrate that PPAR alpha ligands (fenofibrate and WY14,643) suppress hypertrophy-dependent increases in protein synthesis, cell surface area, and sarcomeric organization in vitro. This was accompanied by a decrease in brain natriuretic peptide gene expression, a marker of transcriptional activation in hypertrophy. These effects were equivalent to or greater than those seen with the PPAR gamma agonist rosiglitazone. Fenofibrate and rosiglitazone suppressed endothelin stimulation of human brain natriuretic peptide gene promoter activity, and this effect was amplified by cotransfection of PPAR alpha and PPAR gamma expression vectors, respectively. The fenofibrate-dependent suppression of endothelin's stimulatory activity was dependent upon promoter sequence positioned between -904 and -40 relative to the transcription start site and did not appear to involve a number of positive and negative regulatory elements that are known to govern transcription of this gene. These findings suggest that PPAR alpha ligands could prove to be useful in the management of disorders associated with hypertrophy and remodeling of the myocardium.

Animals↗
PubMed2002

Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.

This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.

Adult↗
PubMed2006

Absence of peroxisome proliferators-activated receptors (PPAR)alpha enhanced the multiple organ failure induced by zymosan.

The peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study is to evaluate the role of PPAR-alpha receptor on the development of multiple-organ dysfunction syndrome (MODS) induced by zymosan. MODS was induced by peritoneal injection of zymosan (dose, 500 mg/kg i.p. as a suspension in saline) in PPAR-alpha wild-type (PPAR-alphaWT) and PPAR-alpha knockout (PPAR-alphaKO) mice, was assessed 18 h after the administration of zymosan, and was monitored for 12 days (for loss of body weight and mortality). A severe inflammatory process, induced by zymosan administration in wild-type mice, coincided with the damage of liver, kidney, pancreas, and small intestine. Myeloperoxidase activity, indicative of neutrophil infiltration, and lipid peroxidation were significantly increased in zymosan-treated wild-type mice. Zymosan in the wild-type mice also induced a significant increase in the plasma levels of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine and Fas ligand in the intestine of zymosan-treated wild-type mice. In contrast, the degree of (1) peritoneal inflammation and tissue injury, (2) nitrotyrosine formation and Fas ligand expression, and (3) neutrophil infiltration were markedly enhanced in intestinal tissue obtained from zymosan-treated PPAR-alphaKO mice. Zymosan-treated PPAR-alphaKO mice also showed a significantly increased mortality. Taken together, the present study clearly demonstrates that PPAR-alpha pathway modulates the degree of MODS associated with zymosan-induced nonseptic shock.

Animals↗
PubMed2003

Activation of PPAR-alpha in streptozotocin-induced diabetes is essential for resistance against acetaminophen toxicity.

Diabetic (DB) mice exhibit significant resistance to hepatotoxicants. The role of peroxisome proliferator receptor (PPAR)-alpha activation in diabetes, in protection against lethal acetaminophen (APAP) challenge, was investigated. Upon treatment with APAP (600 mg/kg, i.p., a LD100 dose in wild-type [WT] non-DB mice), WT-DB mice showed only 30% mortality and 40% less liver injury as measured by alanine aminotransferase and histopathology. In contrast, diabetes in PPAR knockout (PPAR-alpha-/-) mice failed to protect against APAP toxicity, suggesting the importance of PPAR-alpha in diabetes-induced protection. S-phase DNA synthesis and PCNA immunohistochemical staining after injury showed early and robust tissue repair in WT-DB mice, but not in the PPAR-alpha-/--DB mice. Microarray analyses were performed on livers from non-DB and DB (WT and PPAR-alpha-/-) mice at 0 and 12 h after APAP. Microarray data were confirmed via real-time polymerase chain reaction analysis of several genes, including stress response, immediate early genes, DNA damage, heat shock proteins, and cell cycle regulators, followed by Western analyses of selected proteins. Gel shift assays revealed higher activation of nuclear factor-kappaB in WT-DB mice after APAP treatment. These findings suggest PPAR-alpha activation as a hepatoprotective adaptive response mediating protection against APAP in diabetes.

Acetaminophen↗
PubMedDate not supplied

Expression of peroxisome proliferator activated receptors (PPARs) in human hair follicles and PPAR alpha involvement in hair growth.

Peroxisome proliferator-activated receptors (PPARs), which belong to the nuclear hormone receptor superfamily, have recently been described as potent key regulators of epidermal development. As 1,25-dihydroxyvitamin D3, retinoic acid and triiodothyronine are known to exert effects on skin and hair follicle growth through similar receptors, we decided to investigate both the expression pattern of the PPAR alpha, -delta and -gamma subtypes and their role in human hair follicles. Using reverse transcriptase-polymerase chain reaction and immunohistochemistry, we established that PPAR alpha, -delta and -gamma were expressed in both dermal and epithelial human hair follicle cells. Additionally, we evaluated the dose effect of clofibrate, a PPAR alpha ligand, on the survival of human hair follicles in culture. A beneficial effect was observed within a narrow range of concentrations.

Cell Survival↗
PubMed2004

PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)alpha is highly expressed in the heart. PPAR alpha may play a role in cardiac hypertrophy, but effects on cardiac function, inflammation, and fibrosis are unknown. We tested the hypothesis that the PPAR alpha activator fenofibrate prevents myocardial inflammation and fibrosis in angiotensin (Ang) II-infused rats. METHODS AND RESULTS: Sprague Dawley rats received Ang II (120 ng/kg/min subcutaneously), fenofibrate (100 mg/kg/d p.o.), or Ang II + fenofibrate. After 7 d, systolic blood pressure (mmHg) was elevated (P < 0.01) in Ang II-infused rats (173 +/- 4) vs. controls (115 +/- 2) and reduced by fenofibrate (137 +/- 5). Electrophoretic mobility shift assay demonstrated that Ang II upregulated cardiac nuclear factor kappa B activity by 50%. Ang II significantly increased cardiac expression of vascular-cell adhesion molecule-1, platelet endothelial cell adhesion molecule, and intercellular adhesion molecule-1. Increases in expression of these inflammatory mediators were normalized by fenofibrate. Ang II-induced expression of transforming growth factor-beta 1, collagen deposition, and macrophage infiltration were partially prevented by fenofibrate. CONCLUSIONS: The PPAR alpha activator fenofibrate prevented development of hypertension, and improved myocardial inflammation and collagen deposition in Ang II-infused rats. The hypolipidemic drug fenofibrate may be useful in prevention and treatment of myocardial disease associated with hypertension and hyperlipidemia.

Angiotensin II↗
PubMed2004

Prediction of PPAR-alpha ligand-mediated physiological changes using gene expression profiles.

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the transcription of a variety of genes involved in lipid metabolism and is the target receptor for the hypolipidemic drug class of fibrates. In the present study, the molecular and physiological effects of seven different PPAR-activating drugs have been examined in a rodent model of dyslipidemia. The drugs examined were selected to display varying potencies and efficacies toward PPAR-alpha. To help elucidate the link between the gene regulation elicited by PPAR-alpha ligands and the concomitant physiological changes, we have used cDNA microarray analysis to identify smaller gene sets that are predictive of the function of these ligands. A number of genes showed strong correlations to the relative PPAR-alpha efficacy of the drugs. Furthermore, using multivariate analysis, a strong relationship between the drug-induced triglyceride lowering and the transcriptional profiles of the different drugs could be found.

Animals↗
PubMed2005

Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: activation of PPAR-alpha.

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-alpha mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-alpha luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-alpha antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-alpha activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity.

Animals↗
PubMed1996

Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.

Animals↗